Humans develop natural antibodies against a sugar molecule called Gal, which is present on proteins and lipids in most other species. These antibodies represent one of the strongest natural barriers to infection with bacteria, parasites and viruses. NewLink Genetics has licensed this technology as the HyperAcute(c) vaccine and it is in Phase I and II clinical trials as a cancer immunotherapy. In this application, we will use this antibody response as a natural biologic therapy to enhance influenza vaccine candidates. Influenza is a major human health threat and investigation of new vaccine strategies is a priority area of research. There are three specific aims in this proposal. (1) We will examine three different influenza vaccines (hemagglutinin protein, virus-like particles and heat-killed whole virus) with or without addition of the Gal epitopes to determine the vaccination efficacy of this molecule. (2) We will test three different strategies for adding the Gal molecule to a single vaccine in order to determine which modification strategy gives the best vaccine response. (3) We will test the hypothesis that use of Gal containing viral vaccines will enhance the immune response in a preclinical model of immunosenescence. These preclinical studies will be the first step in moving these experiments into a Phase II application where we will refine the best candidate vaccine in preparation for movement into clinical trials. PUBLIC HEALTH RELEVANCE: Influenza is a huge burden for the United States and the world, both in terms of human health and economic losses. The studies in this proposal focus on a novel adjuvant that will facilitate the development of more effective influenza vaccine formulations. We further propose that vaccines devloped with our adjuvant may also increase the immune response to influenza in the elderly. [unreadable] [unreadable] [unreadable]